The present invention relates to novel bis-tetrahydrofuran benzodioxolyl sulfonamide compounds, compositions comprising them and processes for their preparation. It also relates to the use of the present compounds as pharmaceutical active compounds for the therapy and prophylaxis of retroviral infections, particularly HIV infections, and most particularly for multidrug resistant HIV infections in a mammal.
Resistance of HIV against inhibitors is a major cause of therapy failure. Half of the patients receiving anti-HIV combination therapy do not respond fully to the treatment, mainly because of resistance of the virus to one or more drugs used. Moreover, it has been shown that resistant virus is carried over to newly infected individuals, resulting in severely limited therapy options for these drug-naive patients. Therefore, there is a need in the art for new compounds for retrovirus therapy, more particularly for AIDS therapy. The need in the art is particularly acute for compounds that are active not only on wild type virus, but also on the increasingly more common resistant viruses. Moreover, protease inhibitors are commonly administered to AIDS patients in combination with other anti-HIV compounds such as, for instance NRTIs and/or NNRTIs. This causes a high pill burden upon the patient. One way of reducing this pill burden is finding anti-HIV compounds like protease inhibitors with good bioavailability, i.e. a favorable pharmacokinetic and metabolic profile, such that the daily dose can be minimized. Another important characteristic of a good protease inhibitor, and for anti-HIV compounds in general, is that protein plasma binding of the protease inhibitor has minimal or even no effect on its potency.
Several published patent applications disclose HIV protease inhibitors. For instance, WO 95/06030 discloses HIV protease inhibitors with a hydroxyethylamino sulfonamide core structure. Also Ghosh et al. (Bioorganic and Medicinal Chemistry Letters, 8, 1998, 687-690) discloses hydroxyethylamino sulfonamide HIV protease inhibitors.
The compounds of the present invention are surprisingly effective HIV protease inhibitors in terms of their activity over a broad range of HIV mutants and in terms of their bioavailability. Additional objects and advantages will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention. The objects and advantages of the invention will be realized and attained by means of the elements and combinations particularly pointed out in the claims.